Pharmaceutical compositions

ABSTRACT

An anaesthetic composition for use by intravenous injection containing a water-soluble steroidal anaesthetic and a parenterally acceptable non-ionic surface active agent.

United States Patent [191 Davis et al.

1451 Aug. 19, 1975 PHARMACEUTICAL COMPOSITIONS [75] Inventors: Benjamin Davis, Chalfont St. Peter; Derek Roger Pearce, Bracknell, both of England [73] Assignee: Glaxo Laboratories Limited,

Greenford, England [22] Filed: Nov. 20, 1972 [21] Appl. No.: 307,851

Related US. Application Data [63] Continuation-in-part of Ser. No. 208,984, Dec. 16,

1971, abandoned.

[30] Foreign Application Priority Data 3,180,797 4/1965 Cacchillo et a1 424/240 X 3,337,400 8/1967 Smith 424/240 3,714,352 1/1973 Davis et a1. 424/243 3,763,195 10/1973 Davis et al. 260/397.45 3,781,435 12/1973 Davis et al. 424/239 3,816,624 6/1974 Davis et al. 424/243 FOREIGN PATENTS OR APPLICATIONS 982,113 2/1965 United Kingdom 6,555 12/1968 France 834,913 5/1960 United Kingdom 941,694 1 1/1963 United Kingdom OTHER PUBLICATIONS Atkinson et al. J. Med. Chem., 8:426-432, (1965), Action of Some Steroids on the Control Nervous System of the Mouse 11, Pharmacology.

Primary Examiner-Shep K. Rose Attorney, Agent, or Firm-Bacon & Thomas [57] ABSTRACT An anaesthetic composition for use by intravenous injection containing a water-soluble steroidal anaesthetic and a parenterally acceptable non-ionic surface active agent.

14 Claims, No Drawings PHARMACEUTICAL. COMPOSITIONS This Application is a continuation-in-part of our application Ser. No. 208,984 filed December 16, 1971, now abandoned.

This invention is concerned with improvements in or relating to anaesthetic compositions containing watersoluble steroid anaesthetics. t

It has long been known that a number of steroids give rise to profound depression of the central nervous system and act pharmacodynamically an anaesthetics or hypnotics. Such compounds have been the subject of considerable study in an attempt to find anaesthetics to replace such substances as thiopentone sodium normally used but well known to be accompanied by some degree of hazard or disadvantage. The literature shows that very many steroid compounds have been studied in this regard. Reviews and discussions of some of the work carried out are to be found, for example, in Methods in Hormone Research (Edited by Ralph I. Dorfman, Vol. III, Part A, Academic Press London and New York 1964, pages 415-475); H. Witzel, Z Vitamin Hormon-Fermentforsch 1959,10, 46-74; H. Selye, Endocrinology, 1942, 30, 437-453; S. K. Figdor et al., J. Pharmacol. Exptl. Therap, 1957, 119, 299-309 and Atkinson et al., J. Med. Chem. 1965, 8, 426-432.

Various compounds of the steroid series possess useful anaesthetic activity upon intravenous injection, such as for example compounds of the pregnane series basically possessing at the 3-position a keto group or a hydroxy group or esterified hydroxy group in the a-or Bconfiguration, a hydrogen atom at the l7-position and an oxygen function at position-20. Various compounds of the androstane series are also steroid anaesthetics for example androstane compoundsv possessing a hydroxy group or an ester derivative thereof in the a-configuration at position-3 and a carboxy function at position- 1 7.

The term pregnane series and androstane series as used herein refer to compounds having the basic ring system of these series and the l9-nor compounds of each series. A number of steroid anaesthetics are water-soluble and may be injected in simple aqueous solution in sufficient quantity to induce or maintain anaesthesia. We use this term water-soluble in the sense that it is conventionally used in the pharmaceutical art, namely to refer to compounds which are sufficiently soluble to form simple aqueous solutions of a suitable concentration and anaesthetic activity for injection. As will be apparent to those skilled in the art in the field of anaesthetics, a steroid anaesthetic of high potency may generally be regarded as water-soluble if it possesses a solubility in water at C of at least 1 mg/ml.

When water-soluble anaesthetic steroids are administered by the intravenous route at relatively high concentrations and overall quantities, as is common in the art, there is a tendency to vein damage and in particular thrombophlebitis, which frequently imposes a limitation on this mode of application. This is notable, for example, in the case of intravenous administration of hydroxydione sodium succinate, which is stated in Martindales Extra Pharmacopoeia as having a serious tendency to cause local vein damage.

It is an object of the present invention to provide anaesthetic compositions for use in human and veterinary medicine containing a water-soluble steroid, the physiological compatibility of which steroid is improved, i.e. the tendency to cause vein damage as above referred to is reduced.

We have now found that the above tendency to cause vein damage on intravenous administration of watersoluble steroid anaesthetics (particularly at relatively high concentrations and overall quantities) can be reduced or even avoided by incorporation in the aqueous solution for injection of a parenterally acceptable nonionic surface active component. Although surfactants have been incorporated into aqueous solutions for intravenous injection containing water-insoluble steroids to aid the dispersion of the latter as suspensions or solutions, they have not, to our knowledge, been incorporated in solutions containing water-soluble steroids where, of course, their surfactant action would not be required as an aid to formulation.

This finding is particularly valuable in permitting water-soluble steroid anaesthetics to'be administered intravenously at the comparatively high concentrations and quantities required to produce the relatively instantaneous induction of anaesthesia which-is their primary function. While intravenous anaesthetics can 'be used both to induce and to maintain anaesthesia, during surgery, they are primarily used in practice toinduce anaesthesia very rapidly prior to administration of,,for example, an inhalation anaesthetic such as ether, halothane, nitrous oxide or trichloroethylene.

According to the invention therefore we provide anaesthetic composition adapted for use in medicine by intravenous injection and containing a water-soluble steroidal anaesthetic said composition further containing a parenterally acceptable nonionic surface active component whereby the physiological compatibility of said steroidal anaesthetic is improved.

The water-soluble steroidal anaesthetics I generally possess at least one solubilising group which will normally be an ionic substituent for example an anionic substituent such as a carboxylate, carbonate, phosphate or pyrophosphate substituent or a cationic substituent such as an ammonium substituent. Where the ionic substituent is an ammonium substituent, this may, for example, be of the formula -N HRR where R and R which may be the same or different, are hydrogen atoms or aliphatic (e.g. a lower alkyl group having l-6 carbon atoms), araliphatic or aromatic groups such as methyl, ethyl, propyl, butyl, benzyl, phenethyl or phenyl groups or R and R may, together with the nitrogen atom to which they are attached, form a heterocyclic ring which may contain substituents or one or more further hetero-atoms, for example, a piperidino or morpholino group.

Anionic solubilising groups will be associated with physiologically acceptable cations, for example, an alkali metal cation or an ammonium cation which may be substituted by, for example, a monoor di-alkyl, hydroxyalkyl. (or polyhydroxyalkyl), aminoalkyl, acyloxyalkyl, aryl or aralkyl group, preferaly containing up to 10 carbon atoms in each group. The substituted ammonium ions may also be derived from heterocyclic bases such as piperidine or morpholine or N-alkyl derivatives thereof. In general, sodium ions or hydroxyalkyl-ammonium ions are preferred. Where the ionic ester groups carries a cationic substituent, there will be anassociated physiologically acceptable anion, which may, for example, be derived from hydrochloric, hy-

drobromic, hydroiodic, sulphuric, phosphoric acid,

succinic, citric, tartaric, maleic acid or methane sul phonic acid.

The term physiologically acceptable as used herein means that the entity concerned does not impart toxicity to the compound concerned at the dosage levels at which it is normally employed.

The ionic solubilising group in water-soluble anaesthetic steroids is generally attached to a side-chain. Such side-chains may, for example, be acyloxy groups, e.g. lower aliphatic (e.g. having l6 carbon atoms) acyloxy groups; ether or alkoximino groups.

The aliphatic chain in such groups may be interrupted by an oxygen atom or an imino group.

Acyloxy groups carrying ionic substituents include, for example, hemisuccinate, hemiglutarate, hemidiglycolate and hemi-N-acetyl L-glutamate groups, preferably associated with sodium ions, amino-acetate and dimethylor diethylaminoacetate groups, preferably associated with chloride or citrate ions, or a piperidin oacetate group, preferably associated with citrate ions.

The anaesthetic steroids herein concerned may possess solubilising groups, or chains carrying such groups, at" various positions. The 3-position may carry, for example, an ionic acyloxy or alkoximino group. For example, in the androstane series the 17,8-position may have an esterified carboxy group carrying an ionic substituent, such as a basic substituent, for example a morpholinoethoxy carbonyl group, preferably associated with citrate, tartrate, phosphate or mesylate ions. In the pregnane series the 2l-position may have, for example, an acyloxy or ether group carrying a basic substituent, such as a diethylor dimethylaminoacetoxy group, for example associated with citrate, tartrate or phosphate ions. In general solubilising groups may be at one or the other of the 3- and 2l-positions in the pregnanes, or at the 3- or l7-positions of the androstanes, substitution at both of these positions being also possible.

Water-soluble anaesthetic steroids also include compounds having a solubilising group at the 2B-position. Apart from such ionic solubilising groups or chains, the steroid may carry further substituents. Thus, for example, where there is at least one ionic group elsewhere in the molecule, the 3-position may carry an oxo or hydroxy group or a non-ionic acyloxy group; a 3- alkyl group may also be present together with a 3- hydroxy or ionic or non-ionic acyloxy group; the 23- position may carry an alkyl, acyloxy (e.g. loweralkanoyloxy groups), ether (e.g. loweralkoxyether), thioether (e.g. loweralkylthioether), cycloalkyl, aryl (e.g. phenyl), aralkyl (e.g. benzyl), hydroxy, nitro, substituted or unsubstituted amino (e.g. monoor dialkylamino, or a saturated, unsaturated or aromatic heterocyclic amino group e.g. morpholino), thiocyanato, azido, sulphonyloxy or acylthio group or a halogen atom or the Za-position may carry an alkyl group or a halogen atom; the l l-position may carry a hydroxy group in the aor B-configuration, if desired together with an aliphatic group such as a lower alkyl or 'allyl group, or an oxo group; the l6-position may carry a halogen atom, e.g. chlorine, or an alkyl (e.g. methyl) group in the ozand/or B-positions. In the pregnanes, whichmay be aor SB-pregnanes, the position may carry an oxo or protected oxo group such as a ketal group, and the 2l-position may carry a hydroxy group, an acyloxy or ether group, a halogen atom, e.g. a chlorine atom, or an aralk yl group such as a benzyl group. Any of these positions may be unsubsti tuted provided one solubilising substituent is present in the molecule.

Acyloxy, ether, alkoximino and alkyl groups which are present preferably possess 1-10 carbon atoms and include, for example, acetyl, pripionyl, methoxy, ethoxy and n-propoxy groups, and methyl groups as well as the ionic groups described above.

Double bands may also be present, for example, at the l-, 4-, 8(9)- or 9(1 1) positions.

Anaesthetic steroids having substituents of the above types are described in commonly Assigned copending applications of Phillipps et al, Ser. No. 197,915 filed Nov. ll, 1971, now US. Pat. No. 3,869,451 dated Mar. 4, 1975, Ser. Nos. 208,961, 208,923 and 208,985 all filed Dec. 16, 1971.

Particularly useful steroids which may be used in the compositions according to the invention are:

2 l -hydroxy-5,B-pregnane3 ,20-dione 2 l hemisuccinate sodium (hydroxydione sodium succinate);

2 l -hydroxy-5/3-pregnane-3 ,20-dione sodium;

3a-hydroxy5B-pregnane-l l ,20-dione hemisuccinate sodium;

3a-hydroxy-5,8-pregnane-20-one sodium;

2 1 -phosphate 3-hemisuccinate 3a-hydroxy5a-pregnane-l 1,20-dione 3- hemisuccinate sodium; 3a-hydroxy-5B-pregnane-l l ,20-dione hemiglutarate sodium; 3a-hydroxyl 6B-methyLSB-pregnane-l l,20-dione,

3-hemisuccinate sodium; 3a-hydroxy-5oz-pregnane-l l ,20-dione tate-hydrochloride;

3a-( DL-oz-amino valeryloxy )-5B-prcgnane-l 1,20-

dione hydrochloride; and

3a( N-B-hydroxyethyl-DL-alanyloxy )-5/3-pregnanel 1,20-dione hydrochloride.

The non-ionic surface active component used in the injectable solutions of the invention preferably has an HLB value (or resultant HLB value) above 9, more preferably above about 12.5. The HLB value of the surface active component is preferably not greater than and more preferably not greater than about 18.

The surface active component may be a mixture of two or more surface active agents, in which case it is the resultant HLB value of the mixture which is of importance,

Particularly useful surfactants for use in accordance with the invention are those carrying a polyoxyethylene grouping, for example:

Polyoxyethylated derivatives of fatty (C l 2-C20) glyceride oils, e.g. castor oil, preferably containing at least (e.g. from 35 to or 60 or more) oxyethylene groups, per mole of fatty oil.

Polyoxyethylene ethers (containing from 10 to 30 oxyethylene groups) of long chain alcohols (containing for example from l2l8 carbon atoms).

Polyoxyethylene-polyoxypropylene ethers preferably containing from 5 to 160, e.g. l5 to 150, oxyethylene and from 15 to oxypropylene groups respectively.

Polyoxyethylated (preferably containing from 15 to 30 oxyethylene groups) fatty acid (e.g. Cl2-l8) esters of sugar alcohol anhydrides e.g. sorbitan or mannitan. Polyethylene glycol ester (preferably containing from 6 to 40 ethylene oxide units) of long chain fatty acids (containing from example l2l8 C atoms) e.g. polye- 3-aminoacethyleneglycol mono-oleate (preferably containing for example 8 ethylene oxide units).

Fatty acid (e.g. Cl2-l8) esters of sugar alcohol anhydrides e.g. sorbitan or mannitan.

Other useful surfactants include phospholipids such as lecithins, e.g. egg or soyabean lecithins.

Examples of non-ionic surface active agents, of the foregoing types, preferred in accordance with the invention include:

Cremophor EL, a polyoxyethylated castor oil containing about 40 ethylene oxide units per triglyceride unit;

Tween 80, polyoxyethylene sorbitan monooleate containing about 20 ethylene oxide units;

Tween 60, polyoxyethylene sorbitan monostearate containing about 20 ethylene oxide units; and

Tween 40, polyoxyethylene sorbitan monopalmitate containing about 20 ethylene oxide units.

Pluronic F68, a block copolymer of ethylene oxide and propylene oxide containing about 150 oxyethylene and about 40 oxy-propylene units. Arlacel 80, sorbitan monooleate.

The concentration of surface active component in the injectable solutions is preferably below 50% and will in general be less than 20% by weight. In general, this maximum quantity will be limited by the physiological acceptability of the surface active component concerned. In fact, it is preferred that thequantity of surface =activecomponent should be less than 10% by weight. In general, the solutions should contain at least 0.1% by weight of surface active component, more preferably above 1.0%. In general the preferred range is 2-5% by weight.

The concentration of the anaesthetic steroid in the solutions will, naturally, vary with the anaesthetic activity of the compound concerned but in general higher concentrations can be employed in the solutions of the invention than have previously been used due to the limitation imposed by the tendency to cause vein damage where a surface active component is not present. In general, the concentration of anaesthetic steroid may be in the range 0.1 to by weight, or conveniently l to 10% by weight.

The injectable solutions of the present invention can contain further physiologically acceptable substances. it may be convenient to include other anaesthetic substances and in view of the presence of the surface active component, it is possible to incorporate waterinsoluble anaesthetic steroids which will be solubilised, that is brought into optically clear solutions, by the surfactant. lt may also be convenient to incorporate a lipophilic substance such as an oil which will again be brought into optically clear solutions by the surfactants if there is a sufiiciently high ratio of surfactant to oil; such oils may enhance the solubility of a waterinsoluble anaesthetic steroid which is present.

It is also possible for an oil to be present in such quantities that it is present in the form of a macroemul sion rather than in the form of the above optically clear solutions or microemulsions.

Other substances which may be present in the injectable solutions of the invention include physiologically acceptable compounds such as sodium chloride, dextrose or glycerol which serve to make the solution substantially isotonic with blood.

As is well known in the anaesthetic art the dose of steroid anaesthetic used to induce anaesthesia will depend on the weight of the individual to be anaesthetised.

Using the compositions of this invention for intravenous administration in the average man a dose of steroid anaesthetic of from 0.25 30 mg/Kg will in general be found to be satisfactory to induce anaesthesia, the preferred dose being generally within the range of from about 0.7 to about 20 mg/Kg. The close will naturally vary to some extent upon the physical condition of the patient, and the degree and period of anaesthesia required, all as is well known in the art. It is thus possible by adjustment of the dose to achieve durations of anaesthesia varying from about 10 minutes to one hour or more. Kit is desired to maintain prolonged anaesthesia, repeated doses of the compositions of the invention may be used, such repeated doses being generally of the same order or lower order than the original dose. Alternatively continuous administration may be undertaken by administering the compounds of the invention at, for example, a rate which will provide from 0.05 2.0, e.g. 0.09 1.8 mg/Kg/Min of the steroid anaesthetic.

The injectable solutions of the invention are preferably presented in dosage unit form, i.e., in containers, for example ampoules or vials, each such container preferably containing from 50 mg to 1000 mg of the water-soluble anaesthetic steroid.

The active drug can alternatively be presented in such vials or ampoules in dry form for reconstitution with an injectable solution of the surface active component. While the dose to be given to any particular patient will, of course, vary with the nature of the active substance and the condition of the patient, dosage units having a content of active ingredient within the above range will provide the medical practitioner, for example, the anaesthetist, with a convenient quantity of the active material in a single dosage, the contents of which will be exactly known. If necessary, the medical practitioner can take fractional doses from such a container.

In order that the invention may be well understood, the following examples are given by way of illustration only:'

EXAMPLE Hydroxydione sodium succinate (500 mg) admixed with 30% by weight of sodium carbonate was dissolved in 5 mls of an aqueous solution containing 20% by weight of Cremophor EL.

EXAMPLE 2 Hydroxydione sodium succinate (500 mg) admixed with 30% by weight of sodium carbonate was dissolved in 10 mls of an aqueous solution containing 10% by weight of Cremophor EL.

EXAMPLE 3 Hydroxydione sodium succinate 500 mg) admixed with 30% by weight of sodium carbonate was dissolved in 20 mls of an aqueous solution containing 5% by weight of Cremophor EL.

EXAMPLE 4 Hydroxydione sodium succinate (500 mg) admixed with 30% by weight of sodium carbonate was dissolved in 50 mls of an aqueous solution containing 2.5% by weight of Cremophor EL.

EXAMPLE 7 Hydroxydione sodium succinate 1000 mg) admixed with 30% by weight of sodium carbonate was dissolved in 20 mls of an aqueous solution containing by weight of Tween 80.

EXAMPLE 8 Hydroxydione sodium succinate (500 mg) admixed with 30% by weight of sodium carbonate was dissolved in 25 mls of an aqueous solution containing 20% by weight of a surfactant mixture which contained by weight-of A'rlacel 80 and 85% by weight Tween 80.

EXAMPLE 9 v 3a-l-lydroxys5fi-pregnane-l 1,20-dione-3- aminoacetatehydrochloride (200 mgs) was dissolved in 5 mls of an aqueous solution containing by weight of Cremophor EL.

EXAMPLE 10 3a( DL-B-amino valeryloxy )-5B-pregnane-1 1,20- dione hydrochloride (200 mgs) was dissolved in 5 mls .of an aqueous solution containing 20% by weight of Cremophor EL.

EXAMPLE 11 3a-(N-B-Hydroxyethyl-DL-alanyloxy)-5,B-pregnane- 1 1,20-dione hydrochloride (500 mgs) was dissolved in 5 mls of an aqueous solution containing 20% by weight of Cremophor EL.

PREPARATION 1 3a-( DL-Z-Aminovaleryloxy)SB-pregnane-1 1,20-dione Hydrochloride A solution of DL-N-Benzyloxycarbonyl-norvaline (1.89g.,) in dry tetrahydrofuran (16 ml.) was treated with a solution of N,N-carbonyldiimidazole 1.22 g.) in dry tetrahydrofuran (16 ml.) and the mixture refluxed for 20 minutes. A solution of 3a-hydroxy-5B-pregnane- 1 1,20-dione 1.66 g.) in dry tetrahydrofuran was added and the mixture refluxed for 4 days. The solvent was removed in vacuo and the residue chromatographed on grade 11] neutral alumina (100 g.), using benzene:- chloroform 2:1 as eluent. Like fractions (on t.l.c.) were combined and evaporated in vacuo. The residual foam was crystallised from ether-petrol (b.p. 40-60) to give 3a-(DL-2-benzyloxy carbonylaminovaleryloxy- )-5B-pregnane-11,20-dione (1.57 g.) as small prisms m.p. l56-158, [a],, 85.5 (c 1.0, dioxan).

A solution of the last-mentioned ester (1.2 g.) in dioxan (60 ml.) with 0.5N-hydrochloric acid (4.24 ml.) and water (6 ml.) was treated with 5% palladium on carbon 600 mg.) and the mixture stirred in a hydrogen stream for 4 hours. The catalyst was removed by filtration and the solution freeze dried. The residual solid was partitioned between water and ether and the aqueous phase separated and evaporated in vacuo to remove traces of ether. The aqueous solution was freeze dried to give title compound (783 mg.) as an amorphous solid, [01],, 101 (c 0.9, H 0).

" PREPARATION 2 3a( N-[ 2-Hydroxyethyl ]-DL-alanyloxy )-5B-pregnane l 1,20-dione hydrochloride A solution 'of 3a-hydroxy-5B-pregnane-l 1,20-dione ml.) -in methylene dichloride (100 ml.) was treated with 2-bromopropionylchloride (3 ml.) and pyridine (4 ml.) and the mixture stored at room temperature of 1 /2 hours. The solution was washed, in turn, with water, ZN-hydrochloric acid, water, saturated aqueous sodium bicarbonae solution and finally with more water, and dried and evaporated in vacuo. The residue, in ether (containing some acetone), was decolourised with charcoal. The solution, after filtering, was treated with petroleum to induce crystallisation. Filtration gave 3a-(DL-2-bromopropionyloxy)- SB-pregnane-l 1,20-dione (6.48g.) as prisms, m.p. l52[a],, 104.5 (c 1.05, dioxan).

A solution of the bromo ester (1.5 g.) in acetonitrile (25 ml.) was treated at 0 with 2-hydroxyethylamine 1.0 g.) and the mixture stored in the refrigerator overnight. The solvent was removed in vacuo and the residue partitioned between ether and water. The organic phase was separated and extracted with cold 2N- hydrochloric acid. The aqueous acid solution was washed with ether and treated with an excess of aqueous sodium bicarbonate solution (at 0) and the liberated base extracted into ether. The ether was removed in vacuo and the residue (1.27 g.) dissolved in dioxan and taken to pH 3 with N-hydrochloric acid. The mixture was freeze dried and the resulting white amorphous solid taken up in water and the aqueous phase washed with ethyl acetate and ether. The aqueous solution was freeze dried (after evaporation in vacuo to remove traces of organic solvent) to give the pure title compound (970 mg.) as an amorphous solid, m.p. ca. 50, [a],,+ 102.2 (c 1.0, H 0).

We claim:

1. An aqueous solution adapted for use in medicine to produce anaesthesia by intravenous injection, said solution consisting essentially of from 01-20% by weight, of a steroidal anaesthetic having a solubility in water at 20C of at least 1 mg/ml and from 01-50% by weight of a vein-damage reducing substance consisting of a parenterally acceptable non-ionic surface active component having an HLB value above 9 and not more than 30, whereby the physiological compatibility of said steroidal anaesthetic is improved.

2. A solution as claimed in claim 1 wherein the HLB value is from 12.5 to 18.

3. A .solution as claimed in claim 1 wherein the surface active component comprises a polyoxyethylated derivative of a fatty glyceride oil, having 12-20 carbon atoms, and containing 35 to 45 oxyethylene groups per mole of fatty oil; a polyoxyethylene ether of an alcohol having 121 8 carbon atoms and containing 10-30 oxyethylene groups; a polyoxyethylene-polyoxypropylene ether containing 15150 oxyethylene groups and 15 to 50-oxypropylene groups; a polyoxyethylated fatty acid (having 12-18 carbon atoms) ester of sorbitan or mannitan containing 15 30 oxyethylene groups; a polyethylene glycol ester of .a fatty acid having 1218 carbon atoms and containing 640 oxyethylene groups; an ester of a fatty acid having 12-18 carbon atoms of sorbitan or mannitan; or a phospholipid.

4. A solution as claimed in claim 1 wherein the surface active component is present in an amount of 2 to 5% by weight.

5. A solution as claimed in claim 1 wherein the steroidal anaesthetic is present in an amount of l to by weight.

6. A solution as claimed in claim 1 wherein the steroidal anaesthetic is a salt formed between the steroid and v a physiologically acceptable anion or cation.

7. A solution as claimed in claim 6 wherein the ionic substituent is a carboxylate, carbonate, phosphate, pyrophosphate or basis substituent.

8. A solution as claimed in claim 6 wherein the steroidal anaesthetic is a member of the pregnane series said salt being a salt of an ionic substituent carried at the 21- position.

9. A solution as claimed in claim 6 wherein said salt being a salt of an ionic substituent is carried at the 2B- position.

10. A solution as claimed in claim 6 wherein the steroidal anaesthetic is a member of the androstane series said salt being a salt of an ionic substituent carried at the l7B-position.

11. A solution as claimed in claim 6 said salt being a salt of an ionic substituent carried at the 3-position.

12. A solution as claimed in claim 1 wherein the steroidal anaesthetic is 2 1 -phosphate 3oz-hydroxy-5a-pregnane-l l ,20-dione 3- hemisuccinate sodium; 3a-hydroxy-5/3-pregnane-l l,20-dione 3- hemiglutarate sodium; 3a-hydroxyl 6B-methyl-5B-pregnane-l l ,20-dione 3-hemisuccinate sodium; or 3a-hydroxy-5B-pregnane-l l,20-dione 3-amino-acetate-hydrochloride.

13. A method of inducing anaesthesia in an individual, man or animal, whereby the tendency to cause vein damage is reduced, comprising intravenously administering to said individual an aqueous solution consisting essentially of from 0.1 20% by weight of a steroidal anaesthetic having a solubility in water at 20C of at least 1 mg/ml and from 0.l50% by weight of a veindamage reducing substance consisting of a parenterally acceptable nonionic surface active component having an HLB value above 9 and not more than 30.

14. The method of claim 13 wherein said solution contains 2%5% by weight of surface active component. 

1. AN AQUEOUS SOLUTION ADAPTED FOR USE IN MEDICINE TO PRODUCE ANAESTHESIA BY INTRAVENOUS INJECTION, SAID SOLUTION CONSISTING ESSENTIALLY OF FROM 0.1-20% BY WEIGHT OF A STEROIDAL ANAESTHETIC HAVING A SOLUBILITY IN WATER AT 20*C OF AT LEAST 1 MG/ML AND FROM 0.1-50% BY WEIGHT OF A VEIN-DAMAGE REDUCING SUBSTANCE CONSISTING OF A PARENTERALLY ACCEPTABLE NONIONIC SURFACE ACTIVE COMPONENT HAVING AN HLB VALUE ABOVE 9 AND NOT MORE THAN 30, WHEREBY THE PHYSIOLOGICAL COMPATIBILITY OF SAID STEROIDAL ANAESTHETIC IS IMPROVED.
 2. A solution as claimed in claim 1 wherein the HLB value is from 12.5 to
 18. 3. A solution as claimed in claim 1 wherein the surface active component comprises a polyoxyethylated derivative of a fatty glyceride oil, having 12-20 carbon atoms, and containing 35 to 45 oxyethylene groups per mole of fatty oil; a polyoxyethylene ether of an alcohol having 12-18 carbon atoms and containing 10-30 oxyethylene groups; a polyoxyethylene-polyoxypropylene ether containing 15-150 oxyethylene groups and 15 to 50 oxypropylene groups; a polyoxyethylated fatty acid (having 12-18 carbon atoms) ester of sorbitan or mannitan containing 15-30 oxyethylene groups; a polyethylene glycol ester of a fatty acid having 12-18 carbon atoms and containing 6-40 oxyethylene groups; an ester of a fatty acid having 12-18 carbon atoms of sorbitan or mannitan; or a phospholipid.
 4. A solution as claimed in claim 1 wherein the surface active component is present in an amount of 2 to 5% by weight.
 5. A solution as claimed in claim 1 wherein the steroidal anaesthetic is present in an amount of 1 to 10% by weight.
 6. A solution as claimed in claim 1 wherein the steroidal anaesthetic is a salt formed between the steroid and a physiologically acceptable anion or cation.
 7. A solution as claimed in claim 6 wherein the ionic substituent is a carboxylate, carbonate, phosphate, pyrophosphate or basis substituent.
 8. A solution as claimed in claim 6 wherein the steroidal anaesthetic is a member of the pregnane series said salt being a salt of an ionic substituent carried at the 21-position.
 9. A solution as claimed in claim 6 wherein said salt being a salt of an ionic substituent is carried at the 2 Beta -position.
 10. A solution as claimed in claim 6 wherein the steroidal anaesthetic is a member of the androstane series said salt being a salt of an ionic substituent carried at the 17 Beta -position.
 11. A solution as claimed in claim 6 said salt being a salt of an ionic substituent carried at the 3-position.
 12. A solution as claimed in claim 1 wherein the steroidal anaesthetic is 21-hydroxy-5 Beta -pregnane-3,20-dione 21-hemisuccinate sodium; 21-hydroxy-5 Beta -pregnane-3,20-dione 21-phosphate sodium; 3 Alpha -hydroxy-5 Beta -pregnane-11,20-dione 3-hemisuccinate sodium; 3 Alpha -hydroxy-5 Beta -pregnane -20-one 3-hemisuccinate sodium; 3 Alpha -hydroxy-5 Alpha -pregnane-11,20-dione 3-hemisuccinate sodium; 3 Alpha -hydroxy-5 Beta -pregnane-11,20-dione 3-hemiglutarate sodium; 3 Alpha -hydroxy-16 Beta -methyl-5 Beta -pregnane-11,20-dione 3-hemisuccinate sodium; or 3 Alpha -hydroxy-5 Beta -pregnane-11,20-dione 3-amino-acetate-hydrochloride.
 13. A method of inducing anaesthesia in an individual, man or animal, whereby the tendency to cause vein damage is reduced, comprising intravenously administering to said individual an aqueous solution consisting essentially of from 0.1 -20% by weight of a steroidal anaesthetic having a solubility in water at 20*C of at least 1 mg/ml and from 0.1-50% by weight of a vein-damage reducing substance consisting of a parenterally acceptable nonionic surface active component having an HLB value above 9 and not more than
 30. 14. The method of claim 13 wherein said solution contains 2%-5% by weight of surface active component. 